A novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer

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dc.contributor.authorKo, Soyeonko
dc.contributor.authorJung, Kyung Heeko
dc.contributor.authorYoon, Young -Chanko
dc.contributor.authorHan, Beom Seokko
dc.contributor.authorPark, Min Seokko
dc.contributor.authorLee, Yun Jiko
dc.contributor.authorKim, Sang Eunko
dc.contributor.authorCho, Ye Jinko
dc.contributor.authorLee, Pureunchowonko
dc.contributor.authorLim, Joo Hanko
dc.contributor.authorRyu, Ji-Kanko
dc.contributor.authorKim, Kewonko
dc.contributor.authorKim, Tae Youngko
dc.contributor.authorHong, Sungwooko
dc.contributor.authorLee, So Hako
dc.contributor.authorHong, Soon-Sunko
dc.date.accessioned2022-11-02T08:00:17Z-
dc.date.available2022-11-02T08:00:17Z-
dc.date.created2022-11-01-
dc.date.created2022-11-01-
dc.date.issued2022-10-
dc.identifier.citationAMERICAN JOURNAL OF CANCER RESEARCH, v.12, no.9, pp.4326 - 4342-
dc.identifier.urihttp://hdl.handle.net/10203/299280-
dc.description.abstractPancreatic ductal adenocarcinoma (PDAC) is an extracellular matrix (ECM)-rich carcinoma, which pro-motes chemoresistance by inhibiting drug diffusion into the tumor. Discoidin domain receptor 1 (DDR1) increases tumor progression and drug resistance by binding to collagen, a major component of tumor ECM. Therefore, DDR1 inhibition may be helpful in cancer therapeutics by increasing drug delivery efficiency and improving drug sensitiv-ity. In this study, we developed a novel DDR1 inhibitor, KI-301690 and investigated whether it could improve the anticancer activity of gemcitabine, a cytotoxic agent widely used for the treatment of pancreatic cancer. KI-301690 synergized with gemcitabine to suppress the growth of pancreatic cancer cells. Importantly, its combination sig-nificantly attenuated the expression of major tumor ECM components including collagen, fibronectin, and vimentin compared to gemcitabine alone. Additionally, this combination effectively decreased mitochondrial membrane po-tential (MMP), thereby inducing apoptosis. Further, the combination synergistically inhibited cell migration and inva-sion. The enhanced anticancer efficacy of the co-treatment could be explained by the inhibition of DDR1/PYK2/FAK signaling, which significantly reduced tumor growth in a pancreatic xenograft model. Our results demonstrate that KI-301690 can inhibit aberrant ECM expression by DDR1/PYK2/FAK signaling pathway blockade and attenuation of ECM-induced chemoresistance observed in desmoplastic pancreatic tumors, resulting in enhanced antitumor effect through effective induction of gemcitabine apoptosis.-
dc.languageEnglish-
dc.publisherE-CENTURY PUBLISHING CORP-
dc.titleA novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer-
dc.typeArticle-
dc.identifier.wosid000863540900016-
dc.type.rimsART-
dc.citation.volume12-
dc.citation.issue9-
dc.citation.beginningpage4326-
dc.citation.endingpage4342-
dc.citation.publicationnameAMERICAN JOURNAL OF CANCER RESEARCH-
dc.contributor.localauthorHong, Sungwoo-
dc.contributor.nonIdAuthorKo, Soyeon-
dc.contributor.nonIdAuthorJung, Kyung Hee-
dc.contributor.nonIdAuthorYoon, Young -Chan-
dc.contributor.nonIdAuthorHan, Beom Seok-
dc.contributor.nonIdAuthorPark, Min Seok-
dc.contributor.nonIdAuthorLee, Yun Ji-
dc.contributor.nonIdAuthorKim, Sang Eun-
dc.contributor.nonIdAuthorCho, Ye Jin-
dc.contributor.nonIdAuthorLee, Pureunchowon-
dc.contributor.nonIdAuthorLim, Joo Han-
dc.contributor.nonIdAuthorRyu, Ji-Kan-
dc.contributor.nonIdAuthorKim, Tae Young-
dc.contributor.nonIdAuthorLee, So Ha-
dc.contributor.nonIdAuthorHong, Soon-Sun-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorDDR1-
dc.subject.keywordAuthorpancreatic cancer-
dc.subject.keywordAuthorECM-
dc.subject.keywordAuthorcollagen-
dc.subject.keywordAuthorgemcitabine-
dc.subject.keywordPlusCELL-SURVIVAL-
dc.subject.keywordPlusKINASE-
dc.subject.keywordPlusIDENTIFICATION-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusSTRATEGY-
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